Zero-order controlled release dosage forms deliver a near-constant concentration of a drug to a patient's body over extended periods of time. This is often desirable for maximum biological effect in particular if a drug exerts its activity by binding and inhibiting a cellular target. In addition, such dosage forms allow for less frequent administration than would be necessary with conventional burst release dosage forms. Furthermore, and of particular importance for ocular and intra-ocular drug delivery the local release provides for high tissue levels in the ocular tissues while minimizing systemic exposure thus minimizing side effects of a drug. Finally, the less frequent administration and continued therapeutic effect increases patient comfort and compliance.
Kohn et al. in U.S. Pat. No. 5,658,995 teaches implants formed from copolymers of tyrosine-based polycarbonates and poly(alkylene oxide). U.S. Pat. No. 5,877,224 discloses polymer-based controlled release drug delivery implants. Kohn et al., U.S. Pat. No. 6,120,491 discloses implantable polymer-based controlled release peptide drug delivery devices formed from polymers derived from the amino acid L-tyrosine. Published U.S. Patent Application No. 2003013848 discloses pharmaceutical formulations for regulating the timed release of biologically active compounds based on a polymer matrix. The disclosures of all four publications are incorporated herein by reference in their entirety.
None of the disclosed publications describe polymer-based controlled release drug delivery implants for water-insoluble drugs providing zero-order drug release. The local delivery of sustained, therapeutically effective concentrations of a drug that is safe, well-tolerated, and suitable for long-term use is a major need within the ophthalmic disease treatment community.
U.S. Pat. No. 6,548,078 discloses methods for treating and/or preventing retinal diseases with sustained release corticosteroids. Complex, multi-layered devices are employed, such as the multi-layered devices disclosed by U.S. Pat. No. 5,378,475.
Simple drug-polymer blends providing pseudo-zero order release are uncommon. Pseudo-zero order release requires a delicate balance between diffusional slow-down and acceleration of the release rate by erosion. It is very difficult to find simple polymer-based formulations that show this behavior in a way that acceleration and deceleration exactly cancel each other over longer periods of time. Individual polymer systems that show such behavior are not predictive of the behavior of other polymer systems. Therefore, there remains a need for biocompatible drug-polymer blends suitable for ocular and intra-ocular drug delivery with pseudo-zero order release kinetics.